The present invention relates to a method of monitoring the role of upper oropharyngeal and laryngeal geometry for the retention and elimination of respiratory drugs when administered by oral inhalation. The method is based primarily upon acquiring real-time MRI images of human subjects while using aerosol inhalation devices. From these image sets and the data accumulated, one may determine design criteria of the delivery device to optimize the delivery of pharmaceutical aerosol to targeted pulmonary sites. Condition variables include particle size, device attributes such as mouthpiece shape and resistance to flow, aerosol exit velocity, and inhalation flow rate.
Magnetic resonance imaging techniques have become widely accepted in medical practice as a means of investigating structural and anatomical differences in body tissues and organs: Justin P. Smith, xe2x80x9cMagnetic Resonance Imaging Using Pattern Recognitionxe2x80x9d U.S. Pat. No. 5,311,131; Hiftje, et al. xe2x80x9cMethod And Device For Spectral Reconstructionxe2x80x9d U.S. Pat. No. 4,642,778; and Shendy et al. xe2x80x9cMethod For Obtaining T1-Weighted and T2-Weighted MNR Images For A Plurality Of Selected Planes In The Course Of A Single Scanxe2x80x9d U.S. Pat. No. 4,734,646. In a typical medical application, a patient is placed within the bore of a large, circular magnet. The magnet creates a static magnetic field that extends along the long (head-to-toe) axis of the patient""s body. An antenna (e.g., a coil of wire) is also positioned within the bore of the large magnet, and is used to create an oscillating radio frequency field that selectively excites hydrogen atoms (protons) in the patient""s body into oscillation. The oscillating field is then turned off, and the antenna is used as a receiving element, to detect the proton oscillations as a function of position within the body. Typically, the intensity of the oscillations is measured throughout a two-dimensional plane. When the intensities are displayed as a function of position in this plane, the result is an image that often bears a striking resemblance to the actual anatomic features in that plane. The intensity of proton oscillations detected at a given point in the patient""s body is proportional to the proton density at that point. Because different types of tissues have different proton densities, different tissue types usually have different image intensities, and therefore appear as distinct structures in the MR image. However, the signal intensity also depends on physical and chemical properties of the tissues being imaged. In a simplified model of MRI, the detected signal intensity, as a function of position coordinates x and y in the plane being imaged, is proportional to
(1xe2x88x92exe2x88x92TR/T1)exe2x88x92TE/T2 
The parameters TR (recovery time) and TE (echo delay time) are under the control of the operator of the MR imaging system, and are constants for any given image. However, T1 and T2 are functions of the tissue under examination, and therefore vary with position in the x-y plane. By suitable selection of parameters TR and TE, either the T1 or the T2 term in the above equation can be made to dominate, thereby producing so-called xe2x80x9cT1-weightedxe2x80x9d and xe2x80x9cT2-weightedxe2x80x9d images, respectively. Other imaging methods, although very effective, have lower resolution and are not nearly as effective in presenting real time data compared to MRI. For example, gamma cameras performing Single Photon Emission Computed Tomography (SPECT) have been utilized in nuclear medicine for some time, but with introduction of high speed digital computer systems for image acquisition as well as image reproduction, images could be acquired and analyzed almost instantaneously. However, SPECT camera systems utilize a collimator that is installed in front of the scintillation crystal within a scintillation detector. The collimator is used to collimate the incoming gamma rays so only those rays of a certain angle of incidence actually penetrate the crystal. Although SPECT imaging is extensively used in nuclear medicine and provides beneficial image quality, the collimator introduces a source of image degradation in nuclear medicine images and tends to somewhat reduce the resolution and quality of images acquired by SPECT systems. For these reasons, the MRI was chosen to follow organic and geometric changes in the airways during aerosol administration.
The respiratory system principally supplies oxygen to the body and removes carbon dioxide from venous blood. It also removes atmospheric contaminants and particulate matter in inspired air entering the large, conducting airways of the respiratory tract. This becomes especially problematic for drugs that are administered by be inhalation to the lung to treat local as well as systemic diseases. Drugs and a variety of insoluble particles that deposit in the conducting zones of the airways may clear out largely by mucocilliary clearance and the cough reflex mechanism, or by endocytosis [Oberdoster G. Lung clearance of inhaled insoluble and soluble particles. J. Aerosol Med. 1988; 1: 289-330]. Therefore, inhaled particles, i.e., cellular debris, degraded myelinate surfactant materials, micro-organisms, and fine particulate drug matter most often are unable to enter the lower and peripheral airways of the lung. If these particles successfully escape the filtration mechanisms of the lung, they could enter the alveoli and acini depending on their size and deposition characteristics.
The lung contains three basic components, namely air, blood and tissue. The architectural arrangement of these three basic components provides optimal conditions for gas exchange and efficient resistance to the movement of air and blood. But a principle function of the lung is to provide for efficient removal of particulate matter in inspired air by a highly specialized transport mechanism referred to as mucocilliary clearance. This is a homeostatic process that can have significant impact on lung drug delivery. Furthermore, the effect of transient changes in airway geometry during the inspiratory maneuver could have considerable impact on drug deposition as well as transport of aerosolized particles from the conducting airways to the respiratory, peripheral lung. To the degree that this is possible, pharmacological actions of inhaled drugs could be significantly altered at their sites of action in the lung or systemically elsewhere in the body. Implications of upper airway anatomy and physiology on morphology of lung drug delivery may be found elsewhere Kilburn K. H., xe2x80x9cFunctional Morphology of The Distal Lungxe2x80x9d, Int. Rev. Cytol. 37 (1974) 153-270. But it is noteworthy that after the oropharynx, the lung splits off dichotomously through 23 generations or branches beginning with the trachea, each subsequent pair of branches having a smaller diameter than that of the parent. A widely used model for describing these geometric and morphologic changes may be obtained from Weibel and others [Weibel, E. R., xe2x80x9cMorphometry of the Human Lungxe2x80x9d, Springer-Verlag, Berlin, (1963) pp. 1-151; Bouhuys A., xe2x80x9cThe Physiology of Breathingxe2x80x9d, Grune and Stratton, 1977, New York, pp. 60-79; 173-232]. Thus, after escaping interception and impaction on the tongue, palate, and larynx, the inhaled particle must travel through a series of tubes with increasing resistance and decreasing diameter. The geometric configuration of the tongue base, and the upfront narrowing of the air gap between the posterior pharyngeal wall and the posterior surface of the tongue base become the first line of defense for the body. Accordingly, the probability with which the inhaled particle is removed from the inspired air before it even has the chance to enter the trachea is greatest in the oropharynx. Thus, it is a significant problem for inhaled drugs to escape filtration mechanisms of the oropharynx during aerosol administration as a normal, homeostatic reflex mechanism triggers interception of solid particles by action of the tongue and palate.
In addition to particulate interception in the oropharynx, the body uses the gag and cough reflexes to functionally remove harmful solids from the inspired air. Additionally, the upper airway produces mucous that traps particles in the air during inspiration and transports them as sputum to the mouth where they are unconsciously swallowed. Reflex action during inhaled drug delivery that provokes swallowing may result in a significant portion of medicament entering the esophagus rather than the lung.
It is therefore a problem for most inhaled aerosols to retain much of their drug payloads in the inspired air until they reach the peripheral lung as a substantial amount of the aerosol cloud, usually in excess of 50%, is lost to the gastrointestinal tract as a result of swallowing. For this reason, the term xe2x80x9cmedication deliveryxe2x80x9d has been devised to refer to the fraction of an aerosolized dose estimated to reach the airways of the patient. It is true that medication delivery efficiency for any aerosol product would depend largely on the device used as a dosimeter. However, gag and cough reflexes are implicated in the inefficiencies associated with aerosol products [Brain D. B., Valberg P. A., and Sneddon S., xe2x80x9cMechanisms of Aerosol Deposition and Clearancexe2x80x9d, in, Aerosols in Medicine, Principles, Diagnostics and Therapy, Morxc3xa9n F, Newhouse M T, and Dolovich M B (eds), Elsevier, 1985, Ch. 5] but these could be avoided largely by good technique during the dosing regime [Newman S P, Pavia D, Garland N, Clarke S W. Effects of various inhalation modes on the deposition of radioactive pressurized aerosols. Eur. J. Respir. Dis., 1982; 63: 57-65]. Generally, proper training is all that may be required in order to substantially reduce dose-variability to an acceptable level. However, with regard to drugs that have a narrow therapeutic index or are too expensive to reasonably accept significant losses from swallowing, dose variability can be reduced only when good device design and good patient technique are used contemporaneously to temporarily decouple the defense mechanisms of the oropharynx [Hilton S. An audit of inhaler technique among asthma patients of 34 general practitioners. Brit. J. Gen. Pract., 1990; 45: 505-506; Pedersen S, Frost L, Arnfred T. Errors in inhalation technique and efficiency in inhaler use in asthmatic children. Allergy, 1986; 41: 118-124; Orehek J, Gayrard P, Grimaud C H, Charpin J. Patient error in use of bronchodilator metered aerosols. Br. Med. J., 1976; 1:76; Newman S P, Pavia D, Clarke S W How should a pressurized xcex2-adrenergic bronchodilator be inhaled ? Eur. J. Respir. Dis., 1981; 62: 3-21].
It is also believed that besides a good device and appropriate technique, the inspiratory maneuver itself, coupled with formulation properties, (i.e., solids content in plume, energetics of aerosolized particles, size, etc), could enhance lung deposition efficiency [Phipps P R, Gonda I. Evaporation of aqueous aerosols produced by jet nebulizers: effects on particle size and concentration of solution in the droplets. J. Aerosol Med., 1994; 7: 239-258; Smalldone G C. Deposition patterns of nebulized drugs: is the pattern important. J. Aerosol Med., 1994: 7(suppl): 25-32; Hurley P K, Smye S W, Cunliffe H. Assessment of antibiotic aerosol generation using commercial jet nebulizers. J. Aerosol Med., 1994; 7: 217-228]. Extreme differences in formulation content and flow rate for different aerosol products (i.e., DPIs, pMDIs, nebulizers) engender significant variations in patient dosing maneuvers. Understandably, these variations result in transient, geometric changes in the oropharynx thus contributing to much of the variability noted earlier for aerosol devices. For some drugs, such noted variability in dose may be acceptable from safety standpoint; however, for drugs demonstrating dose and concentration-dependent adverse events as aerosolized medicines, the liabilities may be considerable when compared with conventional routes of drug administration. For example, inhaled salbutamol and terbutaline require {fraction (1/20)}th of the oral dose to demonstrate equivalent efficacy [E. H. Walter, Res. Clin. Forums, 6, 1984, 73]. Aerosolized beclomethasone diproprionate in doses of 400 xcexcg are reported to be equivalent to 5 to 10 mg of oral prednisolone [D. Ganderton and N. M. Kassem. Dry Powders Inhalers, In: D. Ganderton and T. Jones, eds., Advances in Pharm. Scs., vol. 6, Academic Press, 1992, pp. 165-191]. Effective drug doses in the lung are indeed very low, and for this reason, any significant variations in oropharyngeal removal of the labeled dose may have considerable safety and efficacy concerns.
Attempts have been made to design delivery methods that overcome the restriction caused by breathing and swallowing, but these have been of limited effectiveness. As stated, inspired medicament that impacts in the back of the throat can enter the esophagus rather than the trachea, reducing the dosage going to the desired locations. The hypopharynx leads to both the trachea anteriorly and the esophagus posteriorly. The proximity of these two tubular structures in the back of the mouth make delivery into the trachea and thus to the bronchi and alveoli difficult. This difficulty is further demonstrated by the need to align the axes of the oropharynx, hypoharynx and trachea during endotracheal intubation. Under normal conditions the upper airway is tortuous and, therefore, a poor conduit for visualizing the vocal cords, which is necessary for placement of an artificial airway in patients who are breathing inadequately. The oropharynx is large enough that an orotracheal tube can be easily misdirected by accidental insertion into anatomical spaces surrounding the larynx, such as the esophagus [Aaron E. Bair, xe2x80x9cMethod and apparatus for establishing a surgical airway, U.S. Pat. No. 5,988,168]. Similarly, the oroesophageal axis may be geometrically aligned in such a way as to be counterproductive for aerosol drug delivery such as described earlier. Furthermore, current devices and methods are generally unable to assure the exclusive passage of the aerosol cloud or mouth adapter through or into the intended orifice (the larynx or esophagus).
To overcome dose-triggering and patient inspiratory maneuver difficulties, large medicament holding chambers have been developed as ancillary device hardware for aerosol medicaments. These devices reduce oropharyngeal loss by insuring that only drug particles with a particular size range, i.e., 10 xcexcm or less, are introduced to the orotracheal canal. For example, an auxiliary device that comprises a chamber having an inlet adapted to receive the metered-dose aerosol device, and an outlet has been described (Richard Kraemer, in xe2x80x9cValved auxiliary device for use with aerosol containerxe2x80x9d, U.S. Pat. No. 5,427,089). A mask adapted to communicate with the nose and/or mouth of a patient, preferably an infant or young child, communicates with the chamber outlet via a first valve which permits the infant or young child to inhale aerosol-carrying air from the chamber, and communicates with atmosphere via a second valve permitting exhalation therethrough. The distance between the chamber inlet and the chamber outlet is such that the mass percentage of aerosol particles having a diameter of from 1.0 microns to 5.0 microns is substantially a maximum at the chamber outlet, and the volume of the chamber is from 200-500 ml. Such a device member is large, cumbersome, and user-unfriendly. Although it reduces the effective amount of drug swallowed by the patient, it nonetheless reduces the total medication delivery by retaining the unrespirable fraction of the aerosolized dose.
Inhalation flowrate also has been understood for some time to be an important variable in targeting delivery of inhalation aerosols to particular sites in the pulmonary system. Studies in Bryon (ed.), Respiratory Drug Delivery, CRC Press, Inc. (1990); Newman et al., Thorax, 1981, 36:52-55; Newman et al., Thorax, 1980, 35:234; Newman et al., Eur. J. Respir. Dis., 1981, 62:3-21; and Newman et al., Am. Rev. Respir. Dis., 1981, 124:317-320 indicate that during a single breath of an aerosol compound, only about ten percent of the total aerosol material presented is deposited into the lungs and that the location of deposition in the lung depends upon (1) breath parameters such as volume of inspiration, inspiratory flow rate, breath holding prior to expiration, the lung volume at the time the bolus of medication is administered, and expiratory flow rate, (2) the size, shape and density of the aerosol particles (i.e., the medicinal compound, any carrier, and propellant), and (3) the physiological characteristics of the patient. Present devices and methods cannot eliminate these variables and as such cannot control dosage administration.
A major problem with manual metered dose inhalers is that the patient frequently actuates the device at the incorrect point during the breathing cycle to obtain the benefits of the intended drug therapy or breathes at the wrong flow rate. Thus, patients may inspire too little medication, or take additional doses and receive too much medication or deliver the drug to the throat or mouth rather than the lung. Additionally, currently marketed devices typically produce aerosols with absolute velocities that are significantly higher than a patient can produce via inhalation.
A problem with breath activated drug delivery is that the dose is triggered on crossing a fixed threshold inspiratory effort. Thus, an inspiration effort may be sufficient to release a metered dose, but the inspiratory flow following the release may not be sufficient to cause the aerosol medication to pass into the desired portion of the patient""s airways. Another problem exists with patients whose inspiratory effort is not sufficient to rise above the threshold to trigger the release valve at all.
Laube et al, U.S. Pat. No. 5,320,094, disclose a method of delivering a protein, in particular insulin, to the lungs. The method is characteristic in that an aerosolized mist of small particles is produced in an associated medicament delivery chamber. The distance from the chamber to the patient""s mouth is set to slow the speed of aerosol particles entering the mouth and the flow rate through the chamber is regulated to less than about 30 liters per minute.
Tritle, U.S. Pat. No. 5,203,323, discloses an expansion chamber used in combination with a pMDI to intercept the high-velocity discharge of medicament from a pressurized inhaler. The expansion chamber has a constant volume with no moving parts or external vents for ease of cleaning, for durability and for optimizing the mist concentration. The dimensional parameters of the chamber are optimized to produce a maximum concentration of medicament mist while neutralizing the high velocity of the inhaler discharge. The chamber is provided at one end with an inlet aperture into which the inhaler mouthpiece sealingly fits. At the chamber other end is provided an outlet aperture with a chamber mouthpiece over which a user""s mouth is closed. The chamber mouthpiece aperture is sized so that substantially all of the medicament mist is uniformly withdrawn during a single short breath.
Larson et al., U.S. Pat. No. 5,040,527, discloses an apparatus for dispensing a measured amount of a spray-entrapped product, typically dispensed by a metered dose inhaler device, which includes an elongated passageway having a mouthpiece portion and a main chamber portion. The metered dose inhaler is mounted between the mouthpiece and main chamber portions such that upon operation its spray is directed away from the mouthpiece. A two-position valve is provided to allow a first, low-level flow to be developed through the unit, followed by a higher flow rate as the metered dose inhaler unit is operated. This increased flow, passing through the device in the direction opposite to that of the MDI spray, contacts the spray plume to cause a high level of mixing and a decrease in spray particle size which results in a draw of the spray medication into the lungs of the user.
Zoitan et al., U.S. Pat. No. 4,926,852 discloses an apparatus for use in inhaling pharmaceutical aerosols. The apparatus includes a mouthpiece and a rigid housing for receiving an aerosolized medicine. The rigid housing has one or more orifices, which are spaced from the mouthpiece so that flow through the housing is possible but is limited by the orifice(s) to a desired volumetric flow rate.
Rubsamen, U.S. Pat. No. 5,419,315, discloses an automatic, hand-held, self-contained, portable device for delivering aerosolized drugs into the lung using a pre-programmed microprocessor that avoids overdosing but provides visual and audible signals after successful administration of a dose to the patient. Rubsamen et al, U.S. Pat. Nos. 5,364,838 and 5,672,581 also describe methods for automatically releasing a measured amount of insulin containing formulation into the inspiratory flow path of a patient in response to information obtained from determining a patient""s inspiratory flow rate and volume. U.S. Pat. No. 5,906,202 describes a complex hand held device for effecting the release of medicament coordinated with inspiratory cycle information. The release point is automatically determined either mechanically or, more preferably calculated by a microprocessor which receives data from an electronic sensor. A number of parameters are measured including total lung capacity, inspiratory flow rate and inspiratory volume in order to determine how much aerosol and aerosol free air is to be released, and when in the inspiratory cycle it should be released.
Attempts have been made to solve the patient inspiration synchronization problem. U.S. Pat. No. 4,484,577 refers to using a bi-directional reed whistle to indicate to the patient the maximum rate of inhalation for desired delivery of the drug and flow restrictor to prevent the patient from inhaling too rapidly. U.S. Pat. No. 3,991,304 refers to using biofeedback techniques to train the patient to adopt a desired breathing pattern. U.S. Pat. No. 4,677,975 refers to using audible signals and preselected time delays gated on the detection of inspiratory flow to indicate to the patient when to inhale and exhale, and delivering inhalable material a selected time after the detected onset of flow.
Many other devices have been disclosed in the patent literature, nearly all of these being intended to help with dose coordination and optimization of the lung delivered dose. Most of these devices are complicated, expensive, and often require interaction between the patient and a third party during dose administration. Furthermore, they are unable to neutralize the transient defenses of the oropharynx to intercept and remove medicament from entering the trachea, thus enabling the breakthrough technology described in this application.
Drug formulation approaches have also been used as a means to improve lung drug delivery. Particle deposition in the lung is sensitive to several model-dependent factors. It is important to identify these factors when drawing general conclusions especially in regard to peripheral deposition of drug in the airways. Acute and chronic pulmonary disease can have a dramatic effect on the deposition of medicaments. Many conditions increase airway resistance, making it more difficult to deposit medication in the distal airways. Other conditions reduce lung compliance. Most changes are heterogeneous, occurring in only portions of the lung. Thus medication may go to areas of the lung that are damaged, reducing the effectiveness of pulmonary delivery. Usually, the more chronic and exacerbated the disease state, the greater also is the extent of structural and dimensional changes in the lung. These differences are known to affect airflow and particle deposition during drug therapy with inhalation aerosols [Tzila Zwas S, Katz I, Belfer B, Baum G L, Aharonson E. Scintigraphic monitoring of mucocilliary tracheobronchial clearance of technitium-99m macroaggregated albumin aerosol. J. Nucl. Med., 1987, 28: 161-167]. Lung function parameters (e.g., the movement of air, both volume and velocity) are crucial factors that can affect particle deposition characteristics in patients. These lung function parameters are sensitive to a variety of disease states. For example, airway resistance is compromised in asthma and adult respiratory distress syndrome (ARDS). These disease states could alter deposition patterns of aerosolized particles to the lung compared to lung normal humans. Lung deposition studies during clinical development of aerosolized drugs should thus be carefully designed so that the effects of model-dependent variables, i.e., lung physiology and respiration rate, are kept at a minimum.
Device performance variables, when taken in concert with differences in breathing maneuvers of the patient, can contribute significant intersubject as well as intra-subject variability of the dose to lung. This problem confronts clinicians today, who, in general, tend to indict the aerosol generator or the hardware used to aerosolize these drugs. Hurley et al. showed that respirable fraction (RF) results using gentamicin as model drug with 14 commercial devices varied greatly and related the effect to the type of device used [Hurley P K, Smye S W, Cunliffe H. Assessment of antibiotic aerosol generation using commercial jet nebulizers. J. Aerosol Med., 1994; 7: 217-228; Dahlback M. Behavior of nebulizing solutions and suspensions. J. Aerosol. Med., 1994: 7 (suppl): 13-18]. The RF ranged between 50% with the PulmoNeb device to about 97% for a device sourced from Micro-Cirrus. Considerable differences in the mass output for formulations when nebulized at the same and constant flow rate have also been observed. Here again, the device type appears to be implicated. For example, output of sodium chloride at xcx9c6L/min was found to be only about 60 mg/min with the Ultra Vent device. This mass output appeared to approach 300 mg/min with the Turbo Turret device although both were operated under the same flow rate conditions.
Smaldone et al. [Smaldone G C, Perry R J, Deutsch D G. Characteristics of nebulizers used in the treatment of AIDS-related Pneumocystis carinii pneumonia. J. Aerosol Med., 1988; 1: 113-126] compared the in vitro performance of three nebulizers for the delivery of pentamidine. Each device was tested under conditions recommended for its use, e.g., specific drug concentration and breathing pattern. Apart from the size of the droplets, the potential deposition efficiency for each device was monitored. At a tidal volume of 750 cc and respiration rate of 20 breaths/min, the three nebulizers (AeroTech II, Respigard and Fisoneb) generated droplets with MMAD ranging between 0.8 and 2.5 xcexcm. The differences appear to be significant and suggest that for each device, the deposition efficiency, i.e., the fraction of dose from the nebulizer estimated to deposit in the lung, was generally independent of drug-concentration and rather related to device performance. For example, the deposition efficiency of AeroTech II was found to be highest (xcx9c20%), followed by Fisoneb (xcx9c15%) and then Respigard (5%). The wide differences in deposition efficiency of these devices stress a need for optimal, relevant, and dose to lung discriminating specifications for nebulizers. The results also suggest that nebulized solutions must be approved with specific devices that are indicated on the label to ensure reproducible dose delivery to the peripheral lung.
Thus, precision delivery, control, and repeatability of the dosing maneuver, and systematic estimation of dose to lung, i.e., medication delivery, is a problem for most inhaled medicines. Clearly, inhalation devices should be designed to accommodate these issues. Of particular importance is the development of a device that would ensure targeted delivery of inhalation aerosols over a broad range of patient use patterns and anatomical makeup. Therefore, a method which can be used to acquire information regarding patient performance including the dynamic aspects of anatomical features and flowrate information could be instrumental in evolving device design and improving the precision of targeted pulmonary medication delivery. This disclosure utilizes imaging techniques to identify changes in physiological and geometric alignment of the oropharynx as a means to systemize drug doses received by patients.
It is to be understood that this invention is not limited to the particular methodology, devices and formulations described, as such methods, devices and formulations may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe and disclose specific information for which the reference was cited in connection with.
It is therefore an object of the present invention to provide a method for using a dynamic real-time imaging technique to identify and measure geometric, spatial and anatomical changes in the oropharynx, trachea and/or upper regions of the lungs during aerosol medicament administration.
It is therefore a further object of the present invention to provide a method for measuring inhalation flow rate contemporaneous with a temporal real-time imaging technique that identifies and measures geometric, spatial, and anatomical changes in the oropharynx, trachea and/or upper regions of the lungs during aerosol medicament administration to the body.
It is therefore a still further object of the present invention to use the inhalation flow rate and measured geometric, spatial, and anatomical changes in the oropharynx, trachea and/or upper regions of the lungs during aerosol medicament administration to establish a data base which can yield design criteria for efficient drug delivery.
It is therefore a still further object of the present invention to use the inhalation flow rate and measured geometric, spatial, and anatomical changes in the oropharynx during aerosol administration to establish a data base which can yield an aerosol administration procedure that is insensitive to the gag and cough reflexes so that aerosolized medicament exiting an aerosol generator effectively escapes the filtration and swallowing mechanisms of the oropharynx.
To attain the objects described, there is provided a method comprising the use of magnetic resonance imaging (MRI) where a magnet creates a static magnetic field sufficient to extend along the long (mouth-to-larynx) axis of the patient""s head. The method can also be used to produce images in the upper regions of the lungs and the lower trachea.
Because different types of tissues have different proton densities, different tissue types in the oropharynx, trachea, and lungs will have different image intensities, and therefore appear as distinct structures in the MR image. When this is coupled with the rapid rate at which images are captured, it is evident that the present inventive method provides for the capture of the real-time mobility of these structures during aerosol administration.
The present method also provides flow rate data on medicament administered based upon pressure changes within a testing mouthpiece. The pressure change data is gathered contemporaneous with the capturing of real-time MR images.
The present inventive method enhances understanding of impaction, filtration, and oropharyngeal deposition of inhaled drugs thus allowing quantitation of drug dosimetry based upon geometric and spatial configuration of the larynx/hypopharynx in the anterior-posterior (AP) as well as the cranio-caudal direction during aerosol administration. This method could be further enhanced to evaluate differences between genders, age groups, and healthy volunteers versus patients. This new understanding of the delivery is used to establish a data base of aerosol administration establishing a criteria that can be used to optimize drug delivery to the lungs through better design of delivery devices.